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dc.contributor.authorZhang, S
dc.contributor.authorChang, L
dc.contributor.authorAlfieri, C
dc.contributor.authorZhang, Z
dc.contributor.authorYang, J
dc.contributor.authorMaslen, S
dc.contributor.authorSkehel, M
dc.contributor.authorBarford, D
dc.date.accessioned2020-07-08T09:56:18Z
dc.date.issued2016-05
dc.identifier.citationNature, 2016, 533 (7602), pp. 260 - 264
dc.identifier.issn0028-0836
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3821
dc.identifier.eissn1476-4687en_US
dc.identifier.doi10.1038/nature17973en_US
dc.description.abstractIn eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas phosphorylation of Cdh1 prevents its association with the APC/C. Since both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs, the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto-inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20) rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our results reveal the mechanism for the regulation of mitotic APC/C by phosphorylation and provide a rationale for the development of selective inhibitors of this state.
dc.formatPrint-Electronic
dc.format.extent260 - 264
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.subjectHumans
dc.subjectTosylarginine Methyl Ester
dc.subjectCyclin-Dependent Kinases
dc.subjectCyclins
dc.subjectApoenzymes
dc.subjectCadherins
dc.subjectPhosphoproteins
dc.subjectAntigens, CD
dc.subjectCryoelectron Microscopy
dc.subjectMitosis
dc.subjectBinding Sites
dc.subjectEnzyme Activation
dc.subjectAmino Acid Motifs
dc.subjectProtein Conformation
dc.subjectProtein Binding
dc.subjectPhosphorylation
dc.subjectModels, Molecular
dc.subjectAnaphase-Promoting Complex-Cyclosome
dc.subjectCdc20 Proteins
dc.subjectApc3 Subunit, Anaphase-Promoting Complex-Cyclosome
dc.subjectApc1 Subunit, Anaphase-Promoting Complex-Cyclosome
dc.titleMolecular mechanism of APC/C activation by mitotic phosphorylation.
dc.typeJournal Article
dcterms.dateAccepted2016-04-06
rioxxterms.versionofrecord10.1038/nature17973
rioxxterms.licenseref.startdate2016-05en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature
pubs.issue7602
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Molecular mechanisms of cell cycle regulation
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Molecular mechanisms of cell cycle regulation
pubs.publication-statusPublished
pubs.volume533en_US
pubs.embargo.termsNo embargo
icr.researchteamMolecular mechanisms of cell cycle regulationen_US
dc.contributor.icrauthorAlfieri, Claudioen


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